DESCRIPTION: Five naturally occurring mutations causing obesity have been mapped in the mouse: agouti, obese, diabetes, tub, and fat. This represents an important contribution to understanding the pathophysiology of obesity. The diverse nature of the gene products associated with the obese phenotype suggests that the pathophysiology of obesity is indeed heterogeneous. At the same time, the observation that identical mutations exert different effects in different mouse strains suggest that a panoply of genes interacts with the susceptibility allele. Identification of such interacting or modifier genes is the goal of the present proposal. Because of the heterogeneous and polygenic nature of human obesity, it is not surprising that defects in single genes such as leptin or CPE do not appear to be associated with common forms of obesity in man. The rationale of the present proposal is that the modifier genes may play a more important role in the pathophysiology of common forms of obesity. The fat mutation arose spontaneously in the inbred HRS/J (HRS) strain. The fat mutation had been shown to be associated with hyperinsulinemia. In previous work, the PI showed that hyperinsulinemia in fat mice is primarily due to hyperproinsulinemia, which precedes obesity and is independent of hyperglycemia. CPE is the enzyme required for processing the proinsulin molecule by removing the carboxy-terminal diarginyl residue. In addition, CPE catalyzes processing of other peptide hormones, such as POMC, neurotensin and CCK. A point mutation in the CPE gene causing a single missense mutation in the CPE molecule has been identified as the fat mutation. The correlation between the mutant allele of CPE and the development of obesity is unclear. Interestingly, humans with familial forms of hyperproinsulinemia do not develop obesity, but a single case of a defect in the prohormone convertase gene (PC 1) has been associated with development of massive obesity in man. It is possible that the processing defect affects multiple hormones, thereby causing multiple metabolic defects. Interestingly, the genetic background of the fat mutation affects the phenotype, so that on the HRS background, the fat mutation gives rise to obesity without hyperglycemia, whereas on the C57BLKS/J background (BKS), the fat mutation gives rise to obesity and hyperglycemia.